Enforcing Dirichlet boundary conditions in physics-informed neural networks and variational physics-informed neural networks.

In this paper, we present and compare four methods to enforce Dirichlet boundary conditions in Physics-Informed Neural Networks (PINNs) and Variational Physics-Informed Neural Networks (VPINNs). Such conditions are usually imposed by adding penalization terms in the loss function and properly choosing the corresponding scaling coefficients; however, in practice, this requires an expensive tuning phase. We show through several numerical tests that modifying the output of the neural network to exactly match the prescribed values leads to more efficient and accurate solvers. The best results are achieved by exactly enforcing the Dirichlet boundary conditions by means of an approximate distance function. We also show that variationally imposing the Dirichlet boundary conditions via Nitsche's method leads to suboptimal solvers.

Design and Synthesis of Co-initiators via Base-Catalysed Sequential Conjugate Addition: Application in Photoinduced Radical Polymerisation Reaction.

Applications of photochemistry are becoming very popular in modern-day life due to its operational simplicity, environmentally friendly and economically sustainable nature in comparison to thermochemistry. In particular photoinduced radical polymerisation (PRP) reactions are finding more biological applications and especially in the areas of dental restoration processes, tissue engineering and artificial bone generation. A type-II photoinitiator and co-initiator-promoted PRP turned out to be a cost-effective protocol, and herein we report the design and synthesis of a new efficient co-initiator for a PRP reaction via a barrierless sequential conjugate addition reaction. Experimental mechanistic observations have been further complemented by computational data. Time for newly synthesised 1,2-benzenedithiol (DTH) based co-initiator promoted polymerisation of urethane dimethacrylate (UDMA, 70 %) and triethylene glycol dimethacrylate (TEGDMA, 30 %) in presence of 450 nm LED (15 W) under the aerobic conditions is 38 seconds. Polymeric material has high glass transition temperature, improved mechanical strength (860 BHN) and longer in-depth polymerisation (3 cm).

New insights into the molecular mechanisms of glutaminase C inhibitors in cancer cells using serial room temperature crystallography.

Cancer cells frequently exhibit uncoupling of the glycolytic pathway from the TCA cycle (i.e., the "Warburg effect") and as a result, often become dependent on their ability to increase glutamine catabolism. The mitochondrial enzyme Glutaminase C (GAC) helps to satisfy this 'glutamine addiction' of cancer cells by catalyzing the hydrolysis of glutamine to glutamate, which is then converted to the TCA-cycle intermediate α-ketoglutarate. This makes GAC an intriguing drug target and spurred the molecules derived from bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (the so-called BPTES class of allosteric GAC inhibitors), including CB-839, which is currently in clinical trials. However, none of the drugs targeting GAC are yet approved for cancer treatment and their mechanism of action is not well understood. Here, we shed new light on the underlying basis for the differential potencies exhibited by members of the BPTES/CB-839 family of compounds, which could not previously be explained with standard cryo-cooled X-ray crystal structures of GAC bound to CB-839 or its analogs. Using an emerging technique known as serial room temperature crystallography, we were able to observe clear differences between the binding conformations of inhibitors with significantly different potencies. We also developed a computational model to further elucidate the molecular basis of differential inhibitor potency. We then corroborated the results from our modeling efforts using recently established fluorescence assays that directly read out inhibitor binding to GAC. Together, these findings should aid in future design of more potent GAC inhibitors with better clinical outlook.

Structure of the monotopic membrane protein (S)-mandelate dehydrogenase at 2.2 Šresolution.

The x-ray structure of the monotopic membrane protein (S)-mandelate dehydrogenase (MDH) from Pseudomonas putida reveals an inherent flexibility of its membrane binding segment that might be important for its biological activity. The surface of MDH exhibits a concentration of the positive charges on one side and the negative charges on the other side. The putative membrane binding surface of MDH has a concentric circular ridge, formed by positively charged residues, which projects away from the protein surface by ∼4 Å; this is an unique structural feature and not observed in other monotopic membrane proteins to our knowledge. There are three α-helixes in the membrane binding region. Based on the structure of MDH, it is possible to propose that the interaction of MDH with the membrane is stabilized by coplanar electrostatic interactions, between the positively charged concentric circular ridge and the negatively charged head-groups of the phospholipid bilayer, along with three α-helixes that provide additional stability by inserting into the membrane. The structure reveals the possible orientation of these helixes along with possible roles for the individual residues which form those helixes. These α-helixes may play a role in the enzyme's mobility. A detergent molecule, N-Dodecyl-ß-maltoside, is inserted between the membrane binding region and rest of the molecule and may provide structural stability to intra-protein regions by forming hydrogen bonds and close contacts. From the average B-factor of the MDH structure, it is likely that MDH is highly mobile, which might be essential for its interaction in membrane and non-membrane environments, as its substrate (S)-mandelate, is from the cytoplasm, while its electron acceptor is a component of the membrane electron transport chain.

Small alveolar macrophages are infected preferentially by HIV and exhibit impaired phagocytic function.

HIV-1-infected persons are at higher risk of lower respiratory tract infections than HIV-1-uninfected individuals. This suggests strongly that HIV-infected persons have specific impairment of pulmonary immune responses, but current understanding of how HIV alters pulmonary immunity is incomplete. Alveolar macrophages (AMs), comprising small and large macrophages, are major effectors of innate immunity in the lung. We postulated that HIV-1 impairs pulmonary innate immunity through impairment of AM physiological functions. AMs were obtained by bronchoalveolar lavage from healthy, asymptomatic, antiretroviral therapy-naive HIV-1-infected and HIV-1-uninfected adults. We used novel assays to detect in vivo HIV-infected AMs and to assess AM functions based on the HIV infection status of individual cells. We show that HIV has differential effects on key AM physiological functions, whereby small AMs are infected preferentially by the virus, resulting in selective impairment of phagocytic function. In contrast, HIV has a more generalized effect on AM proteolysis, which does not require direct viral infection. These findings provide new insights into how HIV alters pulmonary innate immunity and the phenotype of AMs that harbors the virus. They underscore the need to clear this HIV reservoir to improve pulmonary immunity and reduce the high incidence of lower respiratory tract infections in HIV-1-infected individuals.

New Group IV chemical motifs for improved dielectric permittivity of polyethylene.

An enhanced dielectric permittivity of polyethylene and related polymers, while not overly sacrificing their excellent insulating properties, is highly desirable for various electrical energy storage applications. In this computational study, we use density functional theory (DFT) in combination with modified group additivity based high throughput techniques to identify promising chemical motifs that can increase the dielectric permittivity of polyethylene. We consider isolated polyethylene chains and allow the CH2 units in the backbone to be replaced by a number of Group IV halides (viz., SiF2, SiCl2, GeF2, GeCl2, SnF2, or SnCl2 units) in a systematic, progressive, and exhaustive manner. The dielectric permittivity of the chemically modified polyethylene chains is determined by employing DFT computations in combination with the effective medium theory for a limited set of compositions and configurations. The underlying chemical trends in the DFT data are first rationalized in terms of various tabulated atomic properties of the constituent atoms. Next, by parametrizing a modified group contribution expansion using the DFT data set, we are able to predict the dielectric permittivity and bandgap of nearly 30,000 systems spanning a much larger part of the configurational and compositional space. Promising motifs which lead to simultaneously large dielectric constant and band gap in the modified polyethylene chains have been identified. Our theoretical work is expected to serve as a possible motivation for future experimental efforts.

Graphs and networks in chemical and biological informatics: past, present and future.

Chemical and biological network analysis has recently garnered intense interest from the perspective of drug design and discovery. While graph theoretic concepts have a long history in chemistry - predating quantum mechanics - and graphical measures of chemical structures date back to the 1970s, it is only recently with the advent of public repositories of information and availability of high-throughput assays and computational resources that network analysis of large-scale chemical networks, such as protein-protein interaction networks, has become possible. Drug design and discovery are undergoing a paradigm shift, from the notion of 'one target, one drug' to a much more nuanced view that relies on multiple sources of information: genomic, proteomic, metabolomic and so on. This holistic view of drug design is an incredibly daunting undertaking still very much in its infancy. Here, we focus on current developments in graph- and network-centric approaches in chemical and biological informatics, with particular reference to applications in the fields of SAR modeling and drug design. Key insights from the past suggest a path forward via visualization and fusion of multiple sources of chemical network data.

Predictive cheminformatics in drug discovery: statistical modeling for analysis of micro-array and gene expression data.

The vast amounts of chemical and biological data available through robotic high-throughput assays and micro-array technologies require computational techniques for visualization, analysis, and predictive -modeling. Predictive cheminformatics and bioinformatics employ statistical methods to mine this data for hidden correlations and to retrieve molecules or genes with desirable biological activity from large databases, for the purpose of drug development. While many statistical methods are commonly employed and widely accessible, their proper use involves due consideration to data representation and preprocessing, model validation and domain of applicability estimation, similarity assessment, the nature of the structure-activity landscape, and model interpretation. This chapter seeks to review these considerations in light of the current state of the art in statistical modeling and to summarize the best practices in predictive cheminformatics.

Bordetella bronchiseptica in a paediatric cystic fibrosis patient: possible transmission from a household cat.

Bordetella bronchiseptica is a zoonotic respiratory pathogen commonly found in domesticated farm and companion animals, including dogs and cats. Here, we report isolation of B. bronchiseptica from a sputum sample of a cystic fibrosis patient recently exposed to a kitten with an acute respiratory illness. Genetic characterization of the isolate and comparison with other isolates of human or feline origin strongly suggest that the kitten was the source of infection.

Exploration of the topology of chemical spaces with network measures.

Discontinuous changes in molecular structure (resulting from continuous transformations of molecular coordinates) lead to changes in chemical properties and biological activities that chemists attempt to describe through structure-activity or structure-property relationships (QSAR/QSPR). Such relationships are commonly envisioned in a continuous high-dimensional space of numerical descriptors, referred to as chemistry space. The choice of descriptors defining coordinates within chemistry space and the choice of similarity metrics thus influence the partitioning of this space into regions corresponding to local structural similarity. These are the regions (known as domains of applicability) most likely to be successfully modeled by a structure-activity relationship. In this work the network topology and scaling relationships of chemistry spaces are first investigated independent of a specific biological activity. Chemistry spaces studied include the ZINC data set, a qHTS PubChem bioassay, as well as the space of protein binding sites from the PDB. The characteristics of these networks are compared and contrasted with those of the bioassay SALI subnetwork, which maps discontinuities or cliffs in the structure-activity landscape. Mapping the locations of activity cliffs and comparing the global characteristics of SALI subnetworks with those of the underlying chemistry space networks generated using different representations, can guide the choice of a better representation. A higher local density of SALI edges with a particular representation indicates a more challenging structure-activity relationship using that fingerprint in that region of chemistry space.

Safety, efficacy and tolerability of exenatide in combination with insulin in the Association of British Clinical Diabetologists nationwide exenatide audit*.

AIM: To assess the extent, safety, efficacy and tolerability of reported off-licence exenatide use through a nationwide audit. METHODS: The Association of British Clinical Diabetologists hosted a password-protected, online collection of anonymized data of exenatide use in real clinical practice. Three hundred and fifteen contributors from 126 centres across UK provided data on 6717 patients. HbA1c and weight changes, exenatide discontinuation, adverse events and treatment satisfaction were compared between non-insulin and insulin-treated patients. RESULTS: Four thousand eight hundred and fifty-seven patients had baseline and follow-up treatment status with mean (±s.d.) baseline HbA1c 9.45 ± 1.69% and BMI 40.0 ± 8.2 kg/m(2) . Of the 4857 patients, 1921 (39.6%) used exenatide with insulin. Comparing patients who continued insulin with exenatide with non-insulin-treated patients, mean (±s.e.) latest HbA1c and weight reduction (median 26 weeks) were 0.51 ± 0.06 versus 0.94 ± 0.04% (p < 0.001) and 5.8 ± 0.2 versus 5.5 ± 0.1 kg (p = 0.278). Insulin-treated patients had higher rates of exenatide discontinuation (31.0 vs. 13.9%, p < 0.001), hypoglycaemia (8.9 vs. 6.1%, p < 0.001), gastrointestinal side effects (28.4 vs. 25.0%, p = 0.008) and treatment dissatisfaction (20.8 vs. 5.7%, p < 0.001). However, 34.2% of the patients continuing insulin still achieved HbA1c reduction ≥1%. There was significant insulin discontinuation, dose reduction and greater sulphonylurea discontinuation among insulin-treated patients. CONCLUSIONS: Addition of exenatide to obese, insulin-treated patients can improve glycaemia and weight. Adverse events were statistically but probably not clinically significantly higher, but combination treatment was less well tolerated. Overall, exenatide was less effective in lowering HbA1c among insulin-treated patients, although significant number of insulin-treated patients still achieved significant HbA1c, weight and insulin reductions. Further research into identifying obese, insulin-treated patients who will tolerate and benefit from exenatide treatment is urgently needed.

A joint x-ray and neutron study on amicyanin reveals the role of protein dynamics in electron transfer.

The joint x-ray/neutron diffraction model of the Type I copper protein, amicyanin from Paracoccus denitrificans was determined at 1.8 A resolution. The protein was crystallized using reagents prepared in D(2)O. About 86% of the amide hydrogen atoms are either partially or fully exchanged, which correlates well with the atomic depth of the amide nitrogen atom and the secondary structure type, but with notable exceptions. Each of the four residues that provide copper ligands is partially deuterated. The model reveals the dynamic nature of the protein, especially around the copper-binding site. A detailed analysis of the presence of deuterated water molecules near the exchange sites indicates that amide hydrogen exchange is primarily due to the flexibility of the protein. Analysis of the electron transfer path through the protein shows that residues in that region are highly dynamic, as judged by hydrogen/deuterium exchange. This could increase the rate of electron transfer by transiently shortening through-space jumps in pathways or by increasing the atomic packing density. Analysis of C-HX bonding reveals previously undefined roles of these relatively weak H bonds, which, when present in sufficient number can collectively influence the structure, redox, and electron transfer properties of amicyanin.

Postcrystallization Analysis of the Irreproducibility of the Human Intrinsic Factor-Cobalamin Complex Crystals.

Approximately 15% (w/w) of human intrinsic factor (IF) is comprised of carbohydrate side chains, making crystallization problematic. In addition, IF is sensitive to proteolysis. To understand the role of these factors in crystallization, we carried out dynamic light scattering studies and assessed their correlation with crystallization. The packing of the IF-cobalamin complex and the known properties of the protein in solution were also analyzed to explore the irreproducibility of the IF-cobalamin complex crystals and the difficulty in obtaining apo-IF crystals suitable for crystallographic analysis. The results indicate that although glycosylation may in general be inhibitory for crystallization, time-dependent proteolysis appears to play a much more important role in the process of crystallization of IF. Thus, the presence of cobalamin and of domain fragments that can form incomplete dimers lacking one of two ß-domains appears to promote the crystallization of IF.

Computational prediction of antibody binding sites on tetracycline antibiotics: electrostatic potentials and average local ionization energies on molecular surfaces.

Enzyme linked immunosorbent assay (ELISA) was used for the analysis of tetracycline, chlortetracycline, oxytetracycline, and their transformed compounds in environmental water samples. The antibodies employed in ELISA showed high relative affinity for tetracycline, epitetracycline, chlortetracycline, and epichlortetracycline as compared to anhydrotetracycline, epianhydrotetracycline, and anhydrochlortetracycline. The specificity and crossreactivity of these antibodies are discussed in relation to the electrostatic potentials and average local ionization energies computed on the molecular surfaces of tetracycline antibiotics and their transformed compounds with an objective of identifying common features as well as differences that may be related to the experimentally observed variation in cross-reactivity values. The computations were performed at both the HF/STO-3G and HF/6-31+G* levels using the Gaussian 98 program. The results in this study are based upon molecular electrostatic potentials and local ionization energies computed on isodensity molecular surfaces. The surface electrostatic potentials are characterized in terms of a group of statistically defined quantities, which include the average deviation, the positive, negative, and total variances, positive and negative surface extrema, and a parameter indicating the degree of electrostatic balance.

Bioinformatics and cheminformatics: where do the twain meet?

Bridging the domains of cheminformatics and bioinformatics in the post-genomic era requires the convergence of goals, tools, techniques and annotations. This article reviews recent research at the interface of the domains that shows evidence of this convergence. While graph theoretical representations have long been used to develop simple topological descriptions of molecules, graph theory-based network concepts are also widely employed in systems biology. Shape and conformation are important for understanding intermolecular interactions, and several structure-based cheminformatic descriptors have been developed and applied to drug-like molecules and biomolecules. Data fusion methods and shared ontologies can also help integrate data from multiple sources in order to generate a holistic picture of the shared molecular informatics domain.

Crystal structure of human intrinsic factor: cobalamin complex at 2.6-A resolution.

The structure of intrinsic factor (IF) in complex with cobalamin (Cbl) was determined at 2.6-A resolution. The overall fold of the molecule is that of an alpha(6)/alpha(6) barrel. It is a two-domain protein, and the Cbl is bound at the interface of the domains in a base-on conformation. Surprisingly, two full-length molecules, each comprising an alpha- and a beta-domain and one Cbl, and two truncated molecules with only an alpha- domain are present in the same asymmetric unit. The environment around Cbl is dominated by uncharged residues, and the sixth coordinate position of Co(2+) is empty. A detailed comparison between the IF-B12 complex and another Cbl transport protein complex, trans-Cbl-B12, has been made. The pH effect on the binding of Cbl analogues in transport proteins is analyzed. A possible basis for the lack of interchangeability of human and rat IF receptors is presented.

Obstructed paraesophageal hernia in a nonagenerian treated by laparoscopic anterior gastropexy.

Paraesophageal hernias have been historically associated with risk of substantial morbidity and mortality. We report a case of a 92 year old lady with acute gastric outlet obstruction due to a chronic paraesophageal hernia that was successfully treated by minimal invasive surgery. Anterior gastropexy was performed after the stomach was reduced. The hiatal opening was enlarged to reduce the risk of obstruction in the future. She was discharged well on the third day.

Initial experience of laparoscopic incisional hernia repair.

Laparoscopic repair of ventral and incisional hernia has become increasingly popular as compared to open repair. The procedure has the advantages of minimal access surgery, reduction of post operative pain and the recurrence rate. A prospective study of laparoscopic incisional hernia repair was performed in our center from August 2002 to April 2004. Eighteen cases (n: 18) were performed during the study period. Fifteen cases (n: 15) had open hernia repair previously. Sixteen patients (n: 16) had successful repair of the hernia with the laparoscopic approach and two cases were converted to open repair. The mean hernia defect size was 156cm2. There was no intraoperative or immediate postoperative complication. The mean operating time was 100 +/- 34 minutes (75 - 180 minutes). The postoperative pain was graded as mild to moderate according to visual analogue score. The mean day of discharge after surgery was two days (1 - 3 days). During follow up, three patients (16.7%) developed seroma at the hernia sac which was resolved with conservative management after three weeks. One (5.6%) patient developed recurrence six months after surgery. In conclusion, laparoscopic repair of incisional hernia particularly recurrent hernia has been shown to be safe and effective in our centre. However, careful patient selection and acquiring the necessary advanced laparoscopic surgical skills coupled with the proper use of equipment are mandatory before embarking on this procedure.

A prospective comparison of percutaneous endoscopic gastrostomy and nasogastric tube feeding in patients with acute dysphagic stroke.

Dysphagia following stroke is common problem and is of particular concern because of its potental for malnutrition. Nasogastric (NG) and percutaneous endoscopic gastrostomy (PEG) tube feeding are recognized methods for nutritional support for patients with persistent neurologic dysphagia. However, the former is associated with tube dislodgement and blockage that might compromise the patients' nutritional status. There have been few randomized prospective studies to date comparing the efficacy and safety of these 2 modes of dysphagia management in stroke patients. The objective of this study was to compare PEG with NG tube feeding after acute dysphagic stroke in terms of nutritional status and treatment failure. This was a randomized prospective clinical trial. A total of 23 consecutive patients who fulfilled the criteria were recruited from the medical wards in Hospital Universiti Kebangsaan Malaysia. The diagnosis of stroke (acute cerebral infarct) was based on clinical and brain computed tomographic (CT scan) findings; and the diagnosis of dysphagia was done clinically by using the 'swallowing test'. At recruitment, upper-arm skin fold thickness (triceps and biceps) and mid-arm circumference were measured; and blood was drawn for serum albumin level. They were then followed up at 4 weeks where the above tests were repeated. A total of 22 patients completed the study (12 patients in the NG group and 10 patients in the PEG group). Serum albumin levels (p = 0.045) were significantly higher in the PEG as compared to the NG group at 4 weeks post-intervention. There were statistically significant improvements in serum albumin level (p = 0.024) in the PEG group; and statistically significant reductions in serum albumin level (p = 0.047) in the NG group 4 weeks after the intervention. However, there were no significant differences in anthropometric parameters between the two groups and no significant changes in these parameters for each group 4 weeks after the intervention. Treatment failure occurred in 5 out of 10 patients (50.0%) in the NG group, but none in PEG group (p = 0.036). PEG tube feeding is more effective than NG tube feeding in improving the nutritional status (in terms of the serum albumin level) of patients with dysphagic stroke. NG tube feeding, in fact, reduced the nutritional status (in terms of the serum albumin level) of the patients.

Role of amino acid properties to determine backbone tau(N-Calpha-C') stretching angle in peptides and proteins.

The analysis of the basic geometry of amino acid residues of protein structures has demonstrated the invariability of all the bond lengths and bond angles except for tau, the backbone N-Calpha-C' angle. This angle can be widened or contracted significantly from the tetrahedral geometry to accommodate various other strains in the structure. In order to accurately determine the cause for this deviation, a survey is made for the tau angles using the peptide structures and the ultrahigh resolution protein structures. The average deviation of N-Calpha-C' angles from tetrahedral geometry for each amino acid in all the categories were calculated and then correlated with forty-eight physiochemical, energetic and conformational properties of amino acids. Linear and multiple regression analysis were carried out between the amino acid deviation and the 48 properties. This study confirms the deviation of tau angles in both the peptide and protein structures but similar forces do not influence them. The peptide structures are influenced by physical properties whereas as expected the conformational properties influence the protein structures. And it is not any single property that dominates the deviation but the combination of different factors contributes to the tau angle deviation.